Warning: Missing argument 2 for wpdb::prepare(), called in /home4/bquality/public_html/wp-content/plugins/membership/membershipincludes/classes/membershippublic.php on line 2303 and defined in /home4/bquality/public_html/wp-includes/wp-db.php on line 1291

Warning: Missing argument 2 for wpdb::prepare(), called in /home4/bquality/public_html/wp-content/plugins/membership/membershipincludes/classes/membershippublic.php on line 2303 and defined in /home4/bquality/public_html/wp-includes/wp-db.php on line 1291Uncategorized | BioQuality.biz - Part 3

Media fill process simulations are a crucial part of demonstrating that an aseptic process remains in a state of control. However, FDA and other regulatory agencies are very demanding when it comes to compliant execution of these studies. Review the items below from recent inspections to make sure you are not making the same mistakes.

483s:

Firm’s media fills are deficient and do not follow the firm’s SOPs for media fills:

Not all the manufacturing operators perform the SOP-specified interventions as required by the procedure

Media filled vials in the area of the interventions are not incubated, and:

Discarding these vials precludes the Quality Init from adequately assessing and assuring that the manual interventions do not create or provide:

adverse conditions that can result in having microbial and /or non-viable contamination

The firm does not have a scientific rationale to support discarding and not incubating the vials from the intervention zone

The firm’s media fill SOP does not permit or discuss discarding of intervention zone vials

Multiple interventions occur simultaneously during routine aseptic filling, but multiple simultaneous interventions are not included in the media fill process simulations

Firm’s media fill process simulations are insufficient to establish that the aseptic process is in control, for example:

the total number of units filled) resulting in inconsistent and inaccurate media fill results

For many studies, the number of units filled did not match the number being evaluated/incubated:

the number of units evaluated/incubated in some media fill runs was smaller than what had been filled

In other media fill runs, the number of units evaluated/incubated was greater than what had been filled. Moreover, firm lacked a justification for these discrepancies

Procedure designed to prevent microbial contamination of drug products purporting to be sterile do not include adequate validation of the sterilization process, specifically:

The firm’s aseptic filling process simulation runs (media fills) designed to validate the aseptic filling of drug product are deficient in that: Modifications to vial filler and restricted access barrier were made after qualification and media fill runs were performed, these modifications were approved without requalification and subsequent successful media fills

Subscribe to BioQuality and keep up with inspection results and much more: www.bioquality.biz

This article provides an overview of emerging detection technologies that provide complementary characterization data encompassing a wider size range of particulates. It also discusses their advantages and limitations in the context of applications in biotherapeutics development. Here are some highlights from the paper:

Protein particulates can form in a wide range of sizes and shapes

Formation of aggregates and particulates in biopharmaceutical formulation continues to be one of the major quality concerns in biotherapeutics development

The presence of large quantities of aggregates is believed to be one of the causes of unwanted immunogenic responses

Comprehensive characterization of particulates in biologics formulation continues to be challenging

However, recent years have seen a significant increase in the development of newer technologies for more comprehensive characterization of particulates

It is well recognized that research on particulates in the submicron (<1 μm) and low-micron (1-10 μm) ranges may provide important clues to understand the mechanism of particulate formation

New molecular entity (NME) approvals by CDER, after a dip down to 20 during fiscal year (FY) 2010, returned, at 30 approvals during FY 2011, to near the FY 2009 level of 31 approvals

Regarding Risk Evaluation and Mitigation Strategies (REMS), the agency released Final Medication Guide Guidance for Industry in November 2011 (http://www.fda.gov/Drugs/DrugSafety/UCM085729)

Recall events for FY 2012, first quarter (99 events), were keeping pace with FY 2011 levels (419 events for the whole year), but the number of recalled products topped 1,100 (1146 products) in the first quarter, on pace to exceed the entire FY 2011 number (1616 products)

The top reasons for major recalls during FY 2010, 2011 and 2012 up to 7-March were:

“Policy changes and enforcement strategies implemented by the FDA have led to an increase in the number of inspections of both Contract Manufacturing Operations (CMOs) and in-house sterile manufacturers — especially injectables,” Barry A Friedman, PhD LLC writes, in an article titled CURRENT CONTRACT MANUFACTURING OPERATION (CMO) REGULATORY ISSUES, on his FDA Warning Letters and USP Updates blog (http://barryafriedmanphdllc.wordpress.com/). He goes on to say that “Contract Manufacturing Operations, in particular, must now have strategies to ensure GMP compliance at their facilities involved in ‘arm’s length’ activities with innovator and generic firms and be prepared for more frequent and thorough audits.” To see the whole article visit the blog, or point your browser to: http://barryafriedmanphdllc.wordpress.com/2012/03/15/current-contract-manufacturing-operation-cmo-regulatory-issues-31512/

——————————————————–

And, talk about the cost of noncompliance, now if you fail an FDA inspection, you really pay. OK, OK, the discussion below is about food, but I think it may also serve as a heads up for drug and biologics firms–FDA has a habit of rolling out new programs in either food or devices and then broadening the application to other regulated products:

Attorney Ricardo Carvajal, writing for the FDA Law Blog (http://www.fdalawblog.net/fda_law_blog_hyman_phelps/), shows how ” Warning letters issued by FDA since late February provide an indication of the types of violations that could trigger reinspection fees under the authority provided by the Food Safety Modernization Act (“FSMA”),” which granted FDA the authority to collect fees for a reinspection after a previous inspection that was classified as Official Action Indicated (OIA). An inspection is classified as OAI if significant objectionable conditions or practices were found and regulatory action is warranted to address non-compliance.

The attorney notes that ” Warning letters to firms subject to reinspection fees now include the following notice:
Section 743 of the Act (21 U.S.C. § 379j-31) authorizes FDA to assess and collect fees to cover FDA’s costs for certain activities, including costs related to re-inspection. A re-inspection is one or more inspections conducted subsequent to an inspection that identified non-compliance materially related to a food safety requirement of the Act, specifically to determine whether compliance has been achieved. Re-inspection-related costs means all expenses, including administrative expenses, incurred in connection with FDA’s arranging, conducting, and evaluating the results of the re-inspection and assessing and collecting the re-inspection fees, 21 U.S.C. § 379j-31(a)(2)(B). For a domestic facility, FDA will assess and collect fees for re-inspection-related costs from the responsible party for the domestic facility. The inspection noted in this letter identified non-compliance materially related to a food safety requirement of the Act. Accordingly, FDA may assess fees to cover any costs related to re-inspection.”

He further advises that “Given the broad range of circumstances under which reinspection fees could be assessed, firms would be well advised to manage their inspections and follow-up corrective actions accordingly.”

The biopharmaceutical industry in China: history and future perspectives, Gao K, Wang J., Front Med. 2012 Apr 28. [Epub ahead of print]
To see the Abstract, and a link to obtain this paper: http://www.ncbi.nlm.nih.gov/pubmed/22544299

Every week, BioQuality Subcribers receive references like these to crucial new papers appearing in the literature. Do you really have the time to do your own searches? Can you afford to miss these papers and the knowledge they contain? Subscribe to BQ at www.bioquality.biz, and rest assured that you will know about any new papers about the topics you care about, including:

Adverse Event Monitoring and Reporting

Analytical Methods for Characterization and Control

At the Cutting Edge

Basic Science Relevant to Biopharma and Biologics

Bioanalytical Methods and Issues

Biological Potency and other Biological Assays

Biomarkers

Biosimilars, Follow-on Biologics, FOPPs, Biobetters, etc.

Business Articles and Reviews (this is actually a section, not a subsection–but it has no subsections under it and thus is listed here and in the QuickScan List)

BioQuality: what you need to know, when you need to know it

FDA has released a Media Fill Guidance Document. The document is aimed at producers of positron emission tomography (PET) drugs, who requested guidance on this subject during meetings with FDA to discuss new regulations going into effect mid-June of this year. However, this guidance, which is in question and answer form, gives advice on media fills that should be of benefit to all involved in aseptic processing.

The media fill questions answered by FDA in the guidance document include:

What is a media fill?

What is the media fill designed to evaluate?

What are the steps involved in a media fill?

How do I choose the growth medium?

How often should a media fill be performed?

A media vendor is typically qualified by testing three batches of medium, How do I do that?

What is growth promotion testing?

What is the difference between growth promotion test and a positive control?

Subscribe to BioQuality, the newsletter that tells you what you need to know, when you need to know it: www.bioquality.biz

Human Tissue Establishment ItelliCell Biosciences received a 6-page Form 483 during an inspection that took placed over 4 days between November 8 and December 12 or last year. Following are some highlights of the 13 deficiency observations, all rather serious, noted by FDA:

Buildings used in the manufacturing and processing of drug product are not maintained in a good state of repair

Records are not kept for the maintenance, cleaning, sanitizing, and inspection of equipment

The control systems necessary to prevent contamination or mix-ups are deficient

There is no quality control unit

Procedures describing the handling of all written and oral complaints regarding a drug product are not established, written, and followed

The distinctive code for each lot of components and drug product containers is not used in recording the disposition ofeach lot

Written procedures are lacking which describe in sufficient detail the receipt, identification, storage, handling, sampling, testing, approval, and rejection of components

Laboratory controls do not include the establishment of scientifically sound and appropriate specifications, standards, sampling plans, and test procedures designed to assure that components, drug product containers, in-process materials, and drug products conform to appropriate standards of identity, strength, quality and purity

Deviations from written production and process control procedures are not justified

Established test procedures and laboratory control mechanisms are not followed and documented at the time of performance

There are no written procedures for production and process controls designed to assure that the drug products have the identity, strength, quality, and purity they purport or are represented to possess

Each batch of drug product required to be free of objectionable microorganisms is not tested through appropriate laboratory testing

Procedures designed to prevent microbiological contamination of drug products purporting to be sterile are not established and written

BioQuality: what you need to know, when you need to know it

At a recent IBC conference titled “BioBetters and BioSimilars: Technologies and Development Strategy”, BioBetter presentations far out-numbered BioSimilar presentations. Is there really more interest in BioBetters? And, by the way, just what is a BioBetter?

According to speaker Bill Strohl, PhD. Vice President Biologics Research from Janssen, a BioBetter is “..a biologic molecule based on the innovator molecule but with improvements intended to increase efficacy, potency, marketability, safety, or patient compliance.”

This is in contrast to next generation products which are based on the same validated target as an innovator biologic but with novel structures (such as the VH/VL chains) and to a BioSimilar, which by definition cannot differ from the comparator product too much. (How much change is too much was a topic raised frequently by meeting attendees.)